Alma Lippi

Pediatric peripheral blood progenitor cell collection: haemonetics MCS 3P versus COBE Spectra versus Fresenius AS104

BACKGROUND: An increasing number of apheresis machines are becoming available for peripheral blood progenitor cell (PBPC) collection in children. STUDY DESIGN AND METHODS: At the Childrens Hospital of Florence (Italy), three apheresis machines were evaluated: MCS 3P (Haemonetics) (10 procedures in 4 patients, aged 10–12 years, weight 23.5‐64 kg), Spectra, (COBE) (8 procedures in 3 patients, aged 4–17 years, weight 19–59 kg), and AS104 (Fresenius) (24 procedures in 9 patients, aged 2–16 years, weight 13.6‐60 kg). For PBPC quantitative analysis, CD34 cytofluorimetry was employed. Relevant variables analyzed included efficiency of CD34+ cell extraction and enrichment, mononuclear cell purity and red cell contamination of the apheresis components, and platelet count decreases after leukapheresis. RESULTS: No significant differences in CD34+ cell‐extraction abilities were found. However, the AS104 provided consistently purer leukapheresis components in terms of mononuclear cell and CD34+ cell enrichment (441 +/− 59%, vs. 240 +/− 35% and 290 +/− 42% for MCS 3P and Spectra, respectively). Postapheresis platelet counts dropped the least with the AS104. The smallest patient who underwent apheresis with MCS 3P (the only machine working on discontinuous flow and hence with greater volume shifts) weighed 23.5 kg and tolerated the procedure well, with no signs of hemodynamic instability. No significant complications were observed. CONCLUSION: All machines seem to have comparable PBPC extraction efficiency, but the AS104 seems to give the component with the greatest PBPC enrichment. This feature might be relevant for further ex vivo cell processing (CD34+ cell selection, expansion, and so on).

G-CSF serum pharmacokinetics during peripheral blood progenitor cell mobilization: neutrophil count-adjusted dosage might potentially improve mobilization and be more cost-effective

The optimal dosing schedule of G-CSF for peripheral blood progenitor cell (PBPC) mobilization is still under investigation although many centers use 10 μg/kg/day in a single subcutaneous dose. However, G-CSF clearance increases with increasing absolute neutrophil count (ANC). Hence a G-CSF dosage adjusted to ANC might be a reasonable approach. We measured G-CSF trough serum levels by sandwich ELISA assay at different ANCs in eight patients undergoing treatment with filgrastim at 10 μg/kg/day in a single subcutaneous dose. A total of 26 samples were analyzed, and a strong correlation between increasing ANC and decreasing G-CSF levels was found by linear regression analysis (P < 0.0003, r2 = 0.4199). For ANC values above 5000/μl the trough serum levels, ie 24 h after administration, were consistently below the level that provides maximal clonogenic precursor stimulation in vitro (10 ng/ml). Serial serum G-CSF measurements performed in three patients at 0, 3, 6, 9 and 24 h after G-CSF administration, showed a reduction of the area under the curve (AUC) with increasing ANC. For an ANC of 20000/μl or greater, the G-CSF serum level fell under the maximal in vitro stimulation threshold of 10 ng/ml within 12 h. This preliminary pharmacokinetic data seems to suggest that an ANC-adjusted G-CSF dosing schedule might improve the design of PBPC mobilization regimens.

Painful procedures in children with cancer: comparison of moderate sedation and general anesthesia for lumbar puncture and bone marrow aspiration.

The study was conducted to compare moderate sedation (MS) with general anesthesia (GA) in the management of frequently performed lumbar puncture or bone marrow aspiration (BMA) during the treatment of childhood cancer.

A single high dose of idarubicin combined with high-dose ARA-C for treatment of first relapse in childhood ‘high-risk’ acute lymphoblastic leukaemia: a study of the AIEOP group

Summary. The outcome of children with acute lymphoblastic leukaemia (ALL) and early relapse remains unsatisfactory. In January 1995, the AIEOP (Associazione Italiana di Oncologia ed Ematologia Pediatrica) group opened a trial for children with ALL in first isolated or combined bone marrow relapse defined at high risk according to the length of first remission and the immunophenotype. The treatment plan included the combination of a single high‐dose idarubicin and high‐dose cytarabine as induction therapy followed by an intensive consolidation and stem cell transplant (SCT). In total, 100 children from 16 Italian centres were enrolled; 80 out of the 99 evaluable patients (81%) achieved second complete remission; eight (8%) died during induction and 11 (11%) failed to respond. A total of 42 out of the 80 responders (52·5%) received a SCT: 19 from an identical sibling, 11 from a matched unrelated donor and 12 from umbilical cord blood cells. The estimated 4‐year overall survival and event‐free survival were 25% and 21% respectively. Disease‐free survival at 4 years was 25·8% for the 80 responders. At 4 years, 39 out of 100 children remain alive, with 27 of them free of leukaemia. This induction therapy has shown antileukaemic efficacy with acceptable toxicity; moreover, all responders proved eligible for intensive consolidation.

Use of percutaneous radial artery catheter for peripheral blood progenitor cell collection in pediatric patients.

BACKGROUND : Leukapheresis procedures require adequate flow rates, which in children may frequently involve invasive vascular access placement.

Pharmacokinetic profile of imatinib mesylate and N-desmethyl-imatinib (CGP 74588) in children with newly diagnosed Ph+ acute leukemias.

Dear Editor, Because of the rarity of childhood Philadelphia chromosome-positive (Ph+) leukemias, data on imatinib pharmacokinetics in children are scant. Imatinib pharmacokinetics were reported in a limited number of leukemic children receiving drug in doses of 260–570 mg/m per day [1]. Despite a wide inter-patient variability, the plasma drug levels were similar to those reported in adult patients treated with standard doses of 400–600 mg/day [2–5]. No data were provided on the pharmacokinetics of the main circulating metabolite of imatinib, N-desmethyl-imatinib (CGP 74588), that had already been determined in adults [2, 6]. Ph+ childhood leukemia is less sensitive to imatinib than adult CML and this is likely to be due to major biological diVerences between these leukemias. However, the diVerent sensitivity may at least partly be related to diVerent bioavailability, metabolism and pharmacokinetic features of imatinib in children and adults that might require adjustment of doses and schedules. In our study, we determined the pharmacokinetics of imatinib and CGP 74588 in three children (two females and one male, aged 11, 15 and 6 years, respectively), with newly diagnosed Ph+ ALL treated according to the induction phase of the EsPhALL (European intergroup study on post-induction treatment of Ph+ ALL) protocol and in one female child (aged 6 years) with CML in lymphoblastic phase. Imatinib was administered at the dosage of 300 mg/m per day in all patients. They were treated in diVerent Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) centers: Monza, Turin and Florence. The Institutionals Ethical Board approved the study, conducted in accordance with the Helsinky declaration of Principle. Patient four merits more detail: male, 6 years old, Ph+ ALL. Three days after starting the induction phase Ib according to the EsPhALL protocol (cyclophosphamide, cytarabine, imatinib 300 mg/m per day £ 28 days administered orally, dissolved in apple juice), the patient developed a neurologic disorder, with asthenia, drowsiness, slowed speech and aphasia, with negative neuroimaging. Chemotherapy and imatinib were suspended, until full spontaneous clinical recovery; 25 days later, imatinib was restarted, initially at half of full dose (a new pharmacokinetic study was carried out when therapy restarted), then 70% and, Wnally, at full dose. This time the drug was taken orally, by swallowing the whole capsule. The patient underwent stem cell transplant and died due to treatment-related toxicity. For the pharmacokinetic study, blood samples were collected at pretreatment (before the morning dose) and 0.5, 1, 2, 4, 8 and 24 h after the Wrst dose and after at least one week of daily doses, presumably when the plasma imatinib concentration achieved steady-state. E. Marangon (&) · F. Sala · M. D’Incalci · M. Zucchetti Laboratory of Cancer Pharmacology, Department of Oncology, Istituto di Ricerche Farmacologiche “Mario Negri”, Milan, Italy e-mail: marangon@marionegri.it

CORRELATION BETWEEN CRANIAL COMPUTED TOMOGRAPHIC SCANS AT DIAGNOSIS IN CHILDREN WITH ACUTE LYMPHOBLASTIC LEUKAEMIA AND CENTRAL NERVOUS SYSTEM RELAPSE

145 children with acute lymphoblastic leukaemia (ALL) were evaluated over a period of 3 years in a multicentre study in which serial cranial computed tomographic (CT) scans of the brain were done. All patients were symptom-free. CT scans were graded as normal, borderline (slight or moderate cerebral atrophy), or pathological (severe cerebral atrophy). 62% (90/145) of children had CT scan abnormalities at diagnosis. After a median follow-up of 24 months (range 6-36) 12 of 108 evaluable patients had central nervous system (CNS) relapses (6 isolated relapses and 6 combined with relapse at another site). All patients with CNS relapse had an abnormal CT scan at diagnosis (8 pathological and 4 borderline). No relapses were observed among the 42 patients with a normal cranial CT scan at diagnosis. A significantly higher proportion of severe cerebral atrophy, both following CNS prophylaxis and after the discontinuation of treatment, was found among patients with a borderline CT scan at diagnosis than among patients with a normal CT scan at diagnosis. Thus an abnormal cranial CT scan at diagnosis in children with ALL seems to have prognostic significance.

t(1;19) and t(12;17) in childhood acute lymphoblastic leukemia of pre-B type

We report on a patient with pre-B acute lymphoblastic leukemia (ALL) and t(t;19) as the principal chromosomal abnormality. The presence of the subsequent t(12;17) and the correlation between the chromosomal anomalies and the immunologic phenotype is discussed.